Nanotechnology Team Captures Tumor Cells in Bloodstream

Vladimir Zharov's team of researchers has discovered a way to capture tumor cells in the bloodstream.

Nov. 17, 2009

A team led by University of Arkansas for Medical Sciences (UAMS) researchers on the cutting edge of nanotechnology has found a way to capture tumor cells in the bloodstream that could dramatically improve earlier cancer diagnosis and prevent deadly metastasis.

The discovery was published Nov. 15 in Nature Nanotechnology, a prestigious monthly print and online journal that provides a forum for leading research papers in all areas of nanoscience and nanotechnology. To read the abstract, click here.

Vladimir Zharov, director of the Phillips Classic Laser and Nanomedicine Laboratory at UAMS, said his team of researchers can inject a cocktail of magnetic and gold nanoparticles with a special biological coating into the bloodstream to target circulating tumor cells. A magnet attached to the skin above peripheral blood vessels can then capture the cells.

“By magnetically collecting most of the tumor cells from blood circulating in vessels throughout the whole body, this new method can potentially increase specificity and sensitivity up to 1,000 times compared to existing technology,” Zharov said.

Once the tumor cells are targeted and captured by the magnet, they can either be microsurgically removed from vessels for further genetic analysis or can be noninvasively eradicated directly in blood vessels by laser irradiation through the skin that is still safe for normal blood cells.

Zharov’s team, which has recently been awarded more than $3.7 million in clinical nanomedicine-related grants, includes Ekaterina Galanzha, M.D., Ph.D., an assistant professor in the UAMS Department of Otolaryngology; Evgeny Shashkov, Ph.D., a visiting scholar and laser physicist; Thomas Kelly, Ph.D., associate professor in the UAMS Department of Pathology; Jin-Woo Kim, Ph.D., a nano-biotechnologist at the University of Arkansas at Fayetteville; and Lily Yang, Ph.D., a biologist from Emory University.

A second related discovery by Zharov’s team was published in Cancer Research in October. It demonstrated that periodic laser irradiation of blood vessels decreases the level of circulating metastatic tumor cells more than 10 times and eventually led to an interruption of metastasis development in distant organs. To read the abstract, click here.

“Further study could determine whether these new cancer treatments are effective enough to be used alone or if they should be used in conjunction with conventional cancer therapy,” Zharov said.

The discovery highlighted in Cancer Research earned Zharov and his team a selection for Faculty of 1000 Biology, an award-winning Web site that highlights and evaluates the most interesting papers published in the biological sciences. Papers are selected based on the recommendations of more than 2000 of the world’s top researchers.

The new discoveries can also be applied for early detection of cancer recurrence and for real-time monitoring therapy efficiency involving the counting of circulating tumor cells.

“Most cancer deaths are the result of metastasis due to the spread of tumor cells from the primary tumor through the blood,” said James Suen, M.D., chairman of the UAMS Winthrop P. Rockefeller Cancer Institute’s Department of Otolaryngology, Head and Neck Surgery. “This revolutionary discovery introduced by Zharov’s team gives many patients hope in earlier cancer diagnosis and better treatment. The nanomedicine-based approach to read and treat whole blood in the body with nanotechnology seems to be universal, with further development holding the promise for the diagnosis and treatment of many diseases, including infections or cardiovascular disorders to prevent stroke and heart attack.”

UAMS is the state’s only comprehensive academic health center, with five colleges, a graduate school, a new 540,000-square-foot hospital, six centers of excellence and a statewide network of regional centers. UAMS has 2,775 students and 748 medical residents. Its centers of excellence include the Winthrop P. Rockefeller Cancer Institute, the Jackson T. Stephens Spine & Neurosciences Institute, the Myeloma Institute for Research and Therapy, the Harvey & Bernice Jones Eye Institute, the Psychiatric Research Institute and the Donald W. Reynolds Institute on Aging. It is the state’s largest public employer with more than 10,000 employees, including nearly 1,150 physicians who provide medical care to patients at UAMS, Arkansas Children’s Hospital, the VA Medical Center and UAMS’ Area Health Education Centers throughout the state. Visit www.uams.edu or www.uamshealth.com.

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Remote-controlled nanocomposite for on-demand drug delivery inside the body

Posted: November 16, 2009

(Nanowerk Spotlight) Quite a number of serious medical conditions, such as cancer, diabetes and chronic pain, require medications that cannot be taken orally, but must be dosed intermittently, on an as-needed basis, and over a long period of time. Researchers have been trying to develop drug delivery techniques with 'on-off switches' that would allow controlled release of drugs into the body. These methods use stimuli such as an implanted heat source or an implanted electronic chip to trigger the drug release from the implanted reservoir. So far, none of these methods can reliably perform all the needed actions: repeatedly turn dosing on and off, deliver consistent doses, and adjust doses according to each patient's need.

By combining magnetism with nanotechnology, researchers have now created a small implantable device that encapsulates the drug in a specially engineered membrane, embedded with magnetic iron oxide nanoparticles. The application of an external, alternating magnetic field heats the magnetic nanoparticles, causing the gels in the membrane to warm and temporarily collapse. This collapse opens up pores that allow the drug to pass through and into the body. When the magnetic field is turned off, the membranes cool and the gels re-expand, closing the pores and halting drug delivery. No implanted electronics are required.

"We have developed an implantable system that can provide on-demand, reproducible drug release whenever the patient – or other operator – wants, for as long as needed, and with the intensity that is desired, using a trigger that is external to the body – in this case an oscillating magnetic field," Daniel Kohane tells Nanowerk. "Most of the previously designed systems could only result in a single release event, or involved implanted triggering systems, or connectors to the outside world."

Kohane, an associate professor of anesthesiology at Harvard Medical School and a senior associate in critical care medicine at Children's Hospital Boston, and his team have reported their findings in a recent issue of Nano Letters ("A Magnetically Triggered Composite Membrane for On-Demand Drug Delivery").

Kohane explains that composite membrane-based drug delivery devices have the potential to greatly increase the flexibility of pharmacotherapy and improve the quality of patients' lives by providing repeated, long-term, on-demand drug delivery for a variety of medical applications, including the treatment of pain (local or systemic anesthetic delivery), local chemotherapy, and insulin delivery.

The membrane that Kohane's team developed consists of ethyl cellulose (the membrane support), superparamagnetic magnetite nanoparticles (the triggering entity), and thermosensitive poly(N-isopropylacrylamide) (PNIPAM)-based nanogels (the switching entity). Membranes were prepared by co-evaporation so that the nanogel and magnetite nanoparticles were entrapped in ethyl cellulose to form a presumably disordered network. To facilitate effective in vivo triggering, the nanogels were engineered to remain swollen (i.e., in the 'off' state) at body temperature.

Stimulus-responsive membrane triggering in vitro: schema of the proposed mechanism of membrane function. (Reprinted with permission from American Chemical Society)

"When we subjected the magnetic nanoparticles embedded in the membrane to an external oscillating magnetic field, they heated inductively," explains Kohane. "The heat generated by magnetite induction heating was transferred to the adjacent thermosensitive nanogels, causing the nanogels to shrink and permit drug diffusion out of the device. When we turned off the magnetic field, the nanogels cooled, causing them to reswell, turning off the drug flow and refilling the membrane pores."

The researchers observed a 10- to 20-fold differential flux between the 'off' and 'on' states. Furthermore, multiple on-off cycles could be performed without significantly changing the permeability of the membrane in the off state.

The on-off action doesn't occur immediately but was much more rapid than that seen with bulk, interpenetrating hydrogel networks. The devices turned 'on' with only a 1-2 minute time lag after the solution temperature reached 40°C and turned 'off' with a 5-10 minute lag after the stimulus was switched off.

Kohane points out that reproducibility will clearly be a key consideration in devices of this type, especially with drugs with narrow therapeutic indices.

"We have shown excellent reproducibility over four magnetically induced cycles" he says. "The maximum number of cycles over which that reproducibility can be maintained remains to be determined, as does the number of cycles over which it needs to be maintained. The latter will depend to a large extent on the specific clinical indication and the expected duration of therapy. Some devices might only need to be triggered a few times, while others – e.g., for a chronic condition requiring treatment several times a day – might require reproducible triggering over thousands of cycles. This issue will be of great importance in the downstream development of the device. Indeed, the ultimate design of a clinical drug delivery device based on this membrane technology, including the specific materials of which it will be composed, is yet to be determined."

By Michael Berger. Copyright 2009 Nanowerk LLC

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Pioneering medical nanotechnology offers new cancer breakthrough hope

Posted on 17 Apr 2009
University of Leicester

A multi-disciplinary team of scientists from the University of Leicester could be potentially paving the way for the development of a powerful new strategy for both the early diagnosis and treatment of prostate cancer.

The research is to use cutting edge nanotechnology to identify a pioneering treatment which could also be applied to other aggressive cancers.

The University of Leicester researchers say that microscopic (5-100 nm) magnetic nanoparticles could be applied in the sensitive diagnosis and effective treatment of prostate cancer. This follows breakthrough nanotechnology research at the University.

Dr Wu Su, of the Department of Chemistry, has been awarded a grant worth £321 K. This is one of only ten Postdoctoral Research Fellowships in the Life Sciences Interface area given this year by the Engineering and Physical Sciences Research Council (EPSRC). This is the first EPSRC postdoctoral research fellowship awarded to the University of Leicester. The highly prestigious award will allow a multi-disciplinary research team to design high-performance magnetic nanoparticles. The team consists of researchers from the University of Leicester departments of Chemistry, Physics, Cancer Studies and Molecular Medicine and Cardiovascular Sciences.

High-performance magnetic nanoparticles act as probes that show up (using Magnetic Resonance Imaging) and kill (by hyperthermia) tumour cells at a much earlier stage than conventional methods.

The pioneering technology, developed at the University of Leicester, is focused on the development of a new type of magnetic nanoparticle in which the magnetic performance is increase by a factor of ten. Targeting these magnetic nanoparticles to unique cell surface receptors present on the prostate tumour cell surface will enable efficient and specific delivery to prostate cancer cells. The approach is general and it is envisaged that these systems could be applied to other types of aggressive cancers [liver, breast, colon] in which early diagnosis and treatment is essential for recovery. Dr Su said this technology requires a multidisciplinary approach: “Prostate cancer cure rates are predicated on early diagnosis and treatment. The technology that we are developing offers the potential of both the identification and treatment of prostate cancer in a highly selective manner.”

Successful implementation of this technology would provide significant welfare benefits for patients [reducing the need for surgical removal of the prostate] and significant cost benefits for the UK health-care system.

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Philips Announce Joint Research to Study Encapsulation of Magnetic Nanoparticles

Philips Research and the University of Urbino (Urbino, Italy) have signed a research agreement to study the encapsulation of magnetic nanoparticle contrast agents inside living blood cells to prolong the retention time of these agents in the blood.

Philips Research and the University of Urbino (Urbino, Italy) will jointly research new contrast agents for medical imaging that are based on the encapsulation of magnetic nanoparticles inside blood cells.

Injected as free particles, magnetic nanoparticle contrast agents are quickly excreted from the blood via the patient's liver, which limits their application. During the collaboration, the University of Urbino will investigate the integration of magnetic nanoparticles into red blood cells and their biological interactions in the human body, while Philips Research will evaluate the properties of these contrast agents in its medical scanners.

The collaboration between Philips Research and the University of Urbino will last for approximately two and a half years, with expected initial applications in the treatment of cardiovascular disease – one of the biggest killers in the western world.

"Nanoparticle blood pool contrast agents have already shown considerable promise in diagnostic imaging, but the short retention time of these particles in the body has always been a real challenge," says Henk van Houten, senior vice president of Philips Research and head of the Healthcare Research program. "Together with the unique expertise of the researchers at the University of Urbino we hope to increase the retention time of these particles from minutes to hours or even days, as this would open up applications such as the image-based monitoring of complex cardiovascular interventions that can take several hours to complete."

This healthcare research alliance follows the recently announced partnerships with West China Hospital in China, the University Medical Centers of Maastricht (the Netherlands) and Aachen (Germany), and the University Medical Center Utrecht in the Netherlands, and is part of Philips' increased commitment to developing solutions for improved patient care. A key success factor for this ambition is the effective translation from new concepts into clinical practice, which requires partnerships with leading academic and medical institutions. Bringing together such partnerships is one of the underlying principles behind Philips’ policy of open innovation.

“Our close collaboration with Philips should speed the translation of our invention into clinical practice,” comments Professor Mauro Magnani, Vice-Rector of the University of Urbino and a project leader of the EU FP6 funded NACBO (Novel and Improved Nanomaterials, Chemistries and Apparatus for Nano-Biotechnology) project. “With our technology, the use of new biomimetic constructs that merge the properties of nanomaterials with those of living cells is finally possible, bringing the real advantages of nanomaterials for therapeutic and diagnostic applications to patients.”

Posted September 24th, 2008

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Pittsburgh researchers developing nanomagnetic cancer therapy

August 6, 2008

Imagine nano-sized magnetic particles capable of fabulous feats such as killing cancer cells in the body, regenerating human tissue and skimming toxic oil spills from lakes and rivers.

Image of oil being pulled by a magnet (last frame) courtesy CMU

Carnegie Mellon University researchers, in collaboration with UPMC Hillman Cancer Center and UPMC McGowan Institute of Regenerative Medicine, are working on pioneering research that may one day save human lives and clean up the environment, all with the help of tiny nanomagnets. They are joined by teams in Berlin and John Hopkins University who are also working toward a breakthrough.

Mike McHenry, professor of material science and engineering at Carnegie Mellon, explains that magnetic nanoparticle research has been ongoing for a decade. The most promising application of this phenomenon is for hyperthermic cancer treatments, heating tissues from 42- to 46-degrees Celsius, a process that selectively eradicates cancer cells while allowing healthy tissue to survive.

“This could be a major breakthrough,” says McHenry. “We wouldn’t have to use chemotherapy to treat cancer, or it could be combined with chemotherapy. The idea is it will enable us to discriminate between healthy and cancerous cells and kill the cancer through a radio frequency field.”

Patients who undergo the localized heat therapy would, at most, experience a warm sensation similar to a high fever, McHenry explains. The research is still in its infancy.

Magnetic nanoparticle dynamics may also be used to reshape and regenerate tissue, research that is in the animal clinical trial stage. With the help of MIT, the biotechnology may also serve as a green method to magnetize and move oil spills from large bodies of water.

The research has been primarily funded through the National Science Foundation.

To see the research in action, click here.

Writer: Debra Smit
Source: Dr. Mike McHenry, Carnegie Mellon University

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Extracting cancer cells with magnetic nanoparticles

By Yun Xie | Published: July 10, 2008 - 09:34AM CT

Cancer metastasis, the spread of cancer cells from their origin to other parts of the body, is often deadly and makes treatments more difficult, as simply removing the primary tumor is often not enough because the cancer cells have circulated to other parts of the body. Metastasis isn't the only problem; surgical procedures can also leave some cells behind, and cancer cells may develop resistance to chemotherapy. All of these issues allow tumors to grow again and increase cancer fatalities. A method of extracting residual and metastatic cancer cells could dramatically improve the long-term survival rate of patients.

Since magnets can function through intervening space and material, magnetic nanoparticles may be the solution to capturing cancer cells. Researchers at the Georgia Institute of Technology investigated the biomedical potential of magnetic nanoparticles for treating ovarian cancer and published their results in July in the Journal of the American Chemical Society.

The new therapeutic approach involves biologically modifying CoFe₂O₄ (cobalt spinel ferrite) nanoparticles. CoFe₂O₄ has been used before for hyperthermia cancer treatment studies, and it responds well to magnetic fields at body temperature. To prevent an immune response, CoFe₂O₄ nanoparticles are layered with polygalacturonic acid, which forms a biocompatible coating. A specific polypeptide, a sequence of amino acids that binds to ovarian cancer cells, was added to the CoFe₂O₄ nanoparticles to ensure selectivity in targeting cells for extraction.

Image Credit: ACS © The American Chemical Society.

To test the efficacy of these modified nanoparticles, the researchers injected ovarian cancer cells into the abdominal cavities of mice. Then, they injected the mice with the magnetic nanoparticles and allowed the nanoparticles to bind to the cancer cells. By using an external magnet (2600 Gauss), the cancer cells could be moved to different locations in the abdominal cavity. Furthermore, when the researchers extracted and magnetically filtered fluids from the abdominal cavity, they found that the nanoparticles selectively targeted ovarian cancer cells.

These results show that magnetic nanoparticles are capable of capturing and removing cancer cells from a live animal, a trick that may nicely complement their ability to deliver drugs to those same cells. Besides ovarian cancer, the nanoparticles can be modified by different types of polypeptides to target a variety of cancers. This approach, when combined with surgery and chemotherapy, has the potential of saving more patients

J. Am. Chem. Soc., 2008. DOI: 10.1021/ja801969b

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Miniaturised scanner zooms in on disease

13:15 08 July 2008

A handheld nuclear magnetic resonance (NMR) scanner that can diagnose diseases and identify pathogens has been built by scientists in the US.

The revolutionary scanner is many times smaller than conventional NMR spectroscopy machines, which require huge magnets to create the powerful magnetic fields necessary to make them work.

Nuclear magnetic resonance spectroscopy works by lining up nuclei in a sample using a powerful magnetic field and then zapping them with radio waves that cause them to wobble, or precess.

This precession induces currents in a nearby coil which can be used to determine the chemical structure of the molecules that contain the nuclei. The same process is used in magnetic resonance imaging machines to make non-invasive images of human bodies. The new device does not produce images, however.

Weaker fields

In conventional NMR spectroscopy machines, powerful fields are necessary to line up individual nuclei.

However, Ralph Weissleder at Harvard Medical School in Cambridge, Massachusetts, US, and colleagues have found that magnetic nanoparticles generate a much larger signal than single nuclei, and can thus be detected using the weaker fields from small permanent magnets.

The trick that Weissleder and colleagues have perfected is to coat these nanoparticles with molecules that bind to specific biomolecules, or bacteria and viruses.

This binding process causes the nanoparticles to clump together, producing a measurable change in the signal they produce. In this way, the team says it can identify a large variety of biological targets.

The team has squeezed the electronics that detect and interpret the signals onto a chip just 2 millimetres square (pdf format).

Small and sensitive

What's more, the researchers have also designed a microfluidics network that shuttles the samples around and concentrates them in volumes of just five millionths of a litre (5 microlitres) – some 60 times less than conventional systems.

"The smaller the system, the better the sensitivity in terms of absolute amount of sample that can be detected," says Hakho Lee, lead author on the research.

The prototype device has eight tiny coils, each of which can monitor nanoparticles sensitive to different biomolecules. Future devices could employ many more such coils.

The result is a prototype machine that is 800 times more sensitive than standard NMR scanners used in many laboratories, says Weissleder.

The team put the prototype through its paces, showing that it is sensitive enough to detect just 10 bacteria in a given sample. By loading each of the eight microcoils with different nanoparticles, the system could distinguish between simulated blood samples representing healthy individuals, those with cancer, and those with diabetes, by looking for eight different biomarker molecules.

Multiple applications

"The biggest advantage is that we don't need sample preparation or purification steps," Lee says. The nanoparticles are simply added to whatever samples are present. "This method could provide an easy and fast way to diagnose almost any kind of disease, such as bacterial infection or cancers in point-of-care settings – right next to the patient or in developing countries."

The device could also be used to test for water purity or even applied to gaseous samples, to search for airborne pathogens or pollutants.

Other researchers are impressed with the work. "If you came to my lab you would see that our spectrometers occupy whole rooms, and we are always struggling with sensitivity in NMR experiments," says Dusan Uhrin, an NMR spectroscopist at the University of Edinburgh.

"They have been able to improve the sensitivity such that they can detect just a few bacteria. It's quite remarkable that they can detect down to that limit," he says.

Weissleder has filed a patent for the design and started a company called T2 Biosystems to market the devices.

Journal reference: Nature Medicine (DOI: 10.1038/nm.1711)

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T2 Biosystems

United States Patent Application 20060269965